A rare but treatable inborn error of metabolism: Arginine glycine amidinotransferase (AGAT) deficiency

AGAT deficiency is a rare and treatable autosomal recessive disorder. The symptoms are early-onset developmental mild to moderate intellectual disability, delayed speech acquisition, behavioral problems or proximal muscle weakness. Biochemical screening for creatine, creatinine and urinary guanidinoacetate and genetic tests are used for diagnosis. Electromyography may be normal or may have a myopathic pattern with low amplitude polyphasic waves. Muscle biopsy may show abnormalities including small myocytes. Creatine supplementation can fully prevent the neurological disability, if the treatment is started early in life; the muscular function improves irrespective of the supplementation moment.

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT−/−) mice and AGAT−/− mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT−/− and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (Ivd, Lcmt2), creatine metabolism (Slc6a8), cerebral myelination (Bcas1) and neuronal excitability (Kcnip3). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8. Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.